Pro Libris: Lubuskie Pismo Literacko-Kulturalne, nr 4 (2010)

145 s. : il., portr.

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Polymeric carbon nitride-based photocathodes for visible light-driven selective reduction of oxygen to hydrogen peroxide

Polymeric carbon nitrides (PCN) are sustainable, tunable, non-toxic and chemically stable materials that represent highly promising heterogeneous photocatalysts for light-driven hydrogen peroxide production via selective reduction of dioxygen. However, most of the studies on photocatalytic H2O2 production using PCN-based photocatalysts reported so far have used PCN powder suspensions and have been carried out in the presence of additional (sacrificial) electron donors, such as aliphatic or aromatic alcohols. Herein, we report the first multicomponent hybrid photocathode based on PCN that is capable of selective reduction of dioxygen to H2O2 under visible light irradiation (420 nm LED). A comparative analysis of various photocathode architectures is carried out using electronic absorption spectroscopy, surface photovoltage spectroscopy, open-circuit photopotential spectroscopy, and photocurrent measurements, including in-situ detection of formed H2O2 using microelectrodes. Notably, the ability of PCN-based photocathodes to catalyze the light-driven reduction of O2 to H2O2 in the absence of any additional electron donor is unambiguously demonstrated. Our study thus highlights the intrinsic nature of the photocatalytic activity of PCN in H2O2 production, and paves the way for the development of further PCN-based photocathodes in which PCN could be coupled with more effective light absorbers to increase the overall performance

Myxoma Virus Expressing a Fusion Protein of Interleukin-15 (IL15) and IL15 Receptor Alpha Has Enhanced Antitumor Activity

<div><p>Myxoma virus, a rabbit poxvirus, can efficiently infect various types of mouse and human cancer cells. It is a strict rabbit-specific pathogen, and is thought to be safe as a therapeutic agent in all non-rabbit hosts tested including mice and humans. Interleukin-15 (IL15) is an immuno-modulatory cytokine with significant potential for stimulating anti-tumor T lymphocytes and NK cells. Co-expression of IL15 with the α subunit of IL15 receptor (IL15Rα) greatly enhances IL15 stability and bioavailability. Therefore, we engineered a new recombinant myxoma virus (vMyx-IL15Rα-tdTr), which expresses an IL15Rα-IL15 fusion protein plus tdTomato red fluorescent reporter protein. Permissive rabbit kidney epithelial (RK-13) cells infected with vMyx-IL15Rα-tdTr expressed and secreted the IL15Rα-IL15 fusion protein. Functional activity was confirmed by demonstrating that the secreted fusion protein stimulated proliferation of cytokine-dependent CTLL-2 cells. Multi-step growth curves showed that murine melanoma (B16-F10 and B16.SIY) cell lines were permissive to vMyx-IL15Rα-tdTr infection. <i>In vivo</i> experiments in RAG1^-/- mice showed that subcutaneous B16-F10 tumors treated with vMyx-IL15Rα-tdTr exhibited attenuated tumor growth and a significant survival benefit for the treated group compared to the PBS control and the control viruses (vMyx-IL15-tdTr and vMyx-tdTr). Immunohistological analysis of the subcutaneous tumors showed dramatically increased infiltration of NK cells in vMyx-IL15Rα-tdTr treated tumors compared to the controls. <i>In vivo</i> experiments with immunocompetent C57BL/6 mice revealed a strong infiltrate of both NK cells and CD8⁺ T cells in response to vMyx-IL15Rα-tdTr, and prolonged survival. We conclude that delivery of IL15Rα-IL15 in a myxoma virus vector stimulates both innate and adaptive components of the immune system.</p></div

Melanoma and glioma cell lines are permissive to recombinant myxoma virus infection.

<p>Cell lines (A) RK-13, (B) GL261, (C) B16-F10, (D) B16.SIY, were infected with either vMyx-tdTr or vMyx-IL15Rα-tdTr at a multiplicity of infection (MOI) of 0.1 to obtain multi-step growth curves. At 0, 12, 24, 48, 72 or 96 h post-infection (p.i.), cells were harvested and lysed, and the viral titer was determined by titration on RK-13 cells. Error bars represent SEM from 3 replicates for each cell line. There was a significant effect of time for each of the cell lines (p<0.001).</p

IL15Rα-IL15 fusion protein is present in the supernatants and extracts of cells infected with vMyx-IL15Rα-tdTr.

<p>Confluent RK-13 cells in 6-well plates were infected with vMyx-IL15Rα-tdTr or vMyx-tdTr at MOI = 5. At indicated times post-infection, media was collected and cells were scraped, lysed and cytoplasmic extract was harvested. Mean ELISA values with SEM for replicates of the same condition are presented, and the experiment was repeated with similar results. There was a significant increase in IL15Rα-IL15 fusion protein in supernatants of vMyx-IL15Rα-tdTr treated cells compared to vMyx-tdTr treated ones at corresponding timepoints (* - p<0.05).</p

Analysis of subsets of T cells infiltrating subcutaneous B16-F10 tumors 3 days after intratumoral virus treatment in C57BL/6 mice.

<p>C57BL/6 mice (n = 3 per group) were implanted with unilateral subcutaneous B16-F10 tumor cells. The first dose of the virus (2.6×10⁷ PFU i.t.) was given on day 7 (when tumors reached approximately 100 mm³) and the second dose was given on day 10. Treatment groups are: 1. vMyx-IL15Rα-tdTr, 2. vMyx-tdTr, 3. PBS. Mice were euthanized 3 days after the final virus treatment and tumor sections were analyzed for presence of T cells by immunostaining for CD4 and CD8 markers. Representative tumor sections are shown. (A) Staining for CD8⁺ T cells in tumors. Green – CD8-positive cells, Blue – DAPI. Scale bar  = 50 micrometers. (B) Staining for CD4⁺ T cells in tumors. Red – CD4-positive cells, Blue – DAPI. Scale bar  = 50 micrometers.</p

NK and T cell infiltration of subcutaneous B16-F10 tumors 3 days after intratumoral virus treatment in C57BL/6 mice.

<p>C57BL/6 mice (n = 3 per group) were implanted with unilateral subcutaneous B16-F10 tumor cells. The first dose of the virus (2.6×10⁷ PFU i.t.) was given on day 7 (when tumors reached approximately 100 mm³) and the second dose was given on day 10. Treatment groups are: 1. vMyx-IL15Rα-tdTr, 2. vMyx-tdTr, 3. PBS. Mice were euthanized 3 days after the final virus treatment and tumor sections were analyzed for presence of NK cells and T cells by immunostaining for Ly-49G2 (4D11 antibody) and CD3, respectively. Representative tumor sections are shown. (A) Staining for NK cells in tumors. Red – 4D11-positive stain, Blue – DAPI. Scale bar  = 50 micrometers. (B) Estimated number of NK cells per square millimeter of a tumor section for each condition, mean values and SEM from 3 mice per group. One-way ANOVA showed significant increase in NK cell accumulation in vMyx-IL15Rα-tdTr treated tumors compared to both vMyx-tdTr and PBS treatments (* - p <0.05). (C) Staining for T cells in tumors. Green – CD3-positive cells, Blue – DAPI. Scale bar  = 50 micrometers. (C) Estimated number of T cells per square millimeter of a tumor section for each condition, mean values and SEM from 3 mice per group. One-way ANOVA showed significant increase in T cell accumulation in vMyx-IL15Rα-tdTr treated tumors compared to both vMyx-tdTr and PBS treatments (* - p<0.05).</p